title: Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar.
abstract: In the present study we have analyzed and compared, by immunohistochemistry and in situ hybridization, the expression pattern of the R4/ALK5 transforming growth factor (TGF)-beta type I receptor (RI) and the TGF-beta type II receptor (RII) in normal human skin, in wounded skin at various stages during the transition of wound granulation tissue to scar, and in long-persisting post-burn hypertrophic scars. In normal human skin, expression of RI and RII was clearly visible in the epidermis, in epidermal appendages, and in vascular cells, although only a small number of dermal fibroblasts revealed detectable levels of TGF-beta receptor expression. In contrast, granulation tissue fibroblasts showed strong expression of both TGF-beta receptor types, although in normal-healing excisional wounds their density decreased during granulation tissue remodeling. However, in post-burn hypertrophic scars, RI- and RII-overexpressing fibroblasts were found in high densities up to 20 months after injury. From these findings we suggest that the repair process of deep wounds involves the transformation of a subset of fibroblastic cells toward an increased TGF-beta responsiveness and a transient accumulation of these cells at the wound site. In addition, our study provides evidence that excessive scarring is associated with a failure to eliminate TGF-beta receptor-overexpressing fibroblasts during granulation tissue remodeling, which leads to a persistent autocrine, positive feedback loop that results in over-production of matrix proteins and subsequent fibrosis.
authors.affiliation: Dermatology Research, Novartis Pharma AG, Basel, Switzerland. peter-1.schmid@pharma.novartis.com
authors.forename: P
authors.initials: P
authors.lastname: Schmid
authors.forename: P
authors.initials: P
authors.lastname: Itin
authors.forename: G
authors.initials: G
authors.lastname: Cherry
authors.forename: C
authors.initials: C
authors.lastname: Bi
authors.forename: D A
authors.initials: DA
authors.lastname: Cox
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D017439:Cicatrix, Hypertrophic / Q000378:metabolism*; D005260:Female; D006097:Granulation Tissue / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta